The present invention relates generally to compounds capable of suppressing immune responses, and more particularly to so-called glycosylation inhibiting factors, which are capable of causing the suppression of immunoglobulin E (IgE) production.
As far as can be determined, the main physiological function of IgE-mediated responses is to combat parasites. The response can be divided into five phases: an IgE-bearing B cell is stimulated to respond to an antigen (phase 1) and activated to secrete IgE antibodies (phase 2); the produced antibodies bind to mast cells and basophils in tissues (phase 3, antibody fixation), interaction of allergen with cell-bound IgE activates these cells, and cause the release of chemical mediators stored in their granules (phase 4, degranulation); and finally, the mediators induce a complex tissue response aimed at the elimination of nonmicrobial parasites from the body (phase 5). Part of this defense mechanism is an attack on the tissue that harbors the parasite--that is, on self. To excise a parasite from a tissue without damaging the rest of the body is an extraordinarily delicate act. The mediators released by activated mast cells and basophils can cause considerable harm, even death, if released at an inappropriate time or if directed at an inappropriate target. The IgE response must be closely controlled and quickly attenuated after its goal has been achieved. As long as this control is functioning there is no danger that healthy parts of the body will be damaged, but should the controls fail, the beneficial reaction will turn into a harmful one. In humans, about 90 percent of all individuals have no difficulty in using their IgE only for defensive purposes; but the remaining unlucky 10 percent carry a genetic defect of the control mechanism that permits the stimulation of IgE responses by antigens that have nothing to do with parasites. At first it was though that this defect was limited only to humans, but similar defects were discovered later in several other mammals. The inappropriately stimulated IgE responses cause a plethora of diverse diseases, grouped under the name allergy or atopy, Klein, Immunology: The Science of Self-Nonself Discrimination (John Wiley & Sons, New York, 1982).
Currently glucocorticoid steroids are the most effective drugs for treating allergic diseases. However prolonged steroid treatment is associated with many deleterious side effects, Goodman and Gillman, The Pharmacological Basis of Therapeutics, 6th ed. (MacMillan Publishing Company, New York, 1980). Recently, Ishizaka and his co-workers have discovered and characterized a class of compounds which they have designated as glycosylation inhibiting factors (GIFs), Ishizaka, Ann. Rev. Immunol., Vol. 2, pgs. 159-182 (1984). GIFs are natural compounds which are capable of causing T cells to produce a class of IgE binding factors which, in turn, selectively suppress the IgE response (IgE suppressive factors). Apparently, one GIF is related to lipomodulin, a phospholipase inhibitory protein, which is induced by treatment of a variety of cells with glucocorticoid, e.g. Flower et al., Nature, Vol. 278, pgs 456-459 (1979). This GIF inhibits the assembly of N-linked oligosaccharide to IgE binding factors for the selective formation of IgE suppressive factors. It suppresses IgE-induced expression of Fc-epsilon receptors on lymphocytes; the factor has a molecular weight of 15-16 kilodaltons, and it binds to monoclonal antibodies against lipomodulin, Uede et al., J. Immunol., Vol. 130, pgs 878-884 (1983), and Iwata et al, J. Immunol., Vol. 132, pgs. 1286-1294 (1984). Wallner, et al., in Nature, Vol. 320, pgs. 77-81 (1986) report the cloning, sequencing and expression of human lipocortin (lipocortin being another name for lipomodulin).
In view of the foregoing it would be advantageous to develop further immunosuppressive compounds, particularly GIFs, which are effective in reducing or eliminating inappropriate IgE responses, but which do not introduce unwanted side effects.